The mammalian peptide Neurokinin B (NKB) belongs to the Tachykinin (TK) peptide family which also includes Substance P (SP) and Neurokinin A (NKA). Pharmacological and molecular biological evidence has shown the existence of three subtypes of TK receptors (NK-1, NK-2 and NK-3). Substance P (also known as NK-1) is a naturally occurring undecapeptide so named due to its prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide produced in mammals and possessing a characteristic amino acid sequence as illustrated in U.S. Pat. No. 4,680,283. Selective peptidic NK-3 receptor antagonists are also known (Drapeau, 1990 Regul. Pept., 31, 125-135).
Given the prevailing involvement of NK-1, efforts to develop antagonists thereto have been ongoing. Among these are the compounds disclosed in U.S. Pat. No. 5,232,929 having the formula:
wherein inter alia R4 and R7 can be H; R2 can be phenyl optionally substituted with halo or alkyl groups; and R3 can be phenyl or naphthyl optionally substituted with halo, nitro, (C1-6)alkyl, (C1-6)alkoxy, trifluoromethyl, phenyl, amino, (C1-6)alkylamino, —(C═O)—NH—(C1-6)alkyl, (C1-6)alkyl-C(═O)—NH—(C1-6)alkyl, —NHC(═O)H and —NHC(═O)—(C1-6)alkyl; specifically cis-3-(2-methoxybenzylamino)-2-phenyl-pyrrolidine.
Additionally, U.S. patent Publication No. 2003/0008892 A1 discloses 3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpyrrolidine.
Notwithstanding, the development of NK-1 antagonists having improved activity and/or stability continues.